Multiple Schlerosis Flashcards
Define Multiple Sclerosis (MS)
“Multiple” - multiple areas of lost myelin
“Sclerosis” - scarring
MS is a chronic AUTOIMMUNE inflammatory disease affecting the CNS
Purpose of myelin sheath and why it’s impactful for MS
Myelin insulate neurons and facilitate nerve conduction efficiency within the CNS.
In MS nerve electrical impulses are affected due to inflammation and immune activity, resulting in demyelination and damage to axons
Multiple Sclerosis (MS) Patient Demographics
Usually:
20-50 years old
2.5 : 1 woman to man ratio
Northern European Descent
More common in people living above 40 degrees latitude (vitamin D component possible)
NOT HEREDITARY
What nutrient/supplement/vitamin may reduce activity of disease in MS?
Vitamin D
Effect of Pregnancy on MS
Seems to have a protective effect
Infections that may trigger MS
Epstein-Barr*, HSV-6, canine distemper, measles, Chlamydia pneumonia
*Dr. Rainka had EB underline, remainder probably not critical to know
Diagnosing Multiple Sclerosis (MS)
At least 2 documented clinical exacerbations separated by time and space as well as 2 distinct MRI lesions separated by time and space.
• Dissemination in time (DIT) - simultaneous presence of gadolinium enhancing lesions (representing inflammation and disease activity) and non-enhancing lesions or a new lesion on a follow-up MRI when compared to a previous MRI.
• Dissemination in space (DIS) - distinctly different anatomical lesions on imaging occurring in areas known to be affected by MS
Clinically Isolated Syndrome (CIS) Diagnosis
CIS is diagnosed after 1 exacerbation and 1 lesion while the clinician awaits a second exacerbation and lesion to be able to make the diagnosis of MS
MS Lesion Appearance Terminology on MRI
“Dawson’s Fingers”
CSF findings indicative of MS
Intrathecal IgG synthesis and Oligoclonal bands (among other findings)
Clinically Isolated Syndrome (CIS) Definition
The first episode of neurologic symptoms lasting at least 24 hours, caused by inflammation and demyelination in one or more sites in the central nervous system. A person with CIS may or may not go on to develop MS
CIS
Clinically Isolated Syndrome
MS
Multiple Sclerosis
RRMS
Relapsing-Remitting Multiple Sclerosis
RRMS Definition / Patient Experiences
• Most common, affecting 85% of patients.
• Patients experience worsening of pre-existing symptoms or onset of new symptoms for periods of greater than 48 hours without concomitant fever, known as relapses, flare-ups, or exacerbations, of MS.
• Contrasted by symptom-free periods, known as remissions, where the patient’s symptoms partially or completely disappear.
Refer to colored graph!
SPMS
Secondary Progressive Multiple Sclerosis
SPMS - Disease Overview
Secondary-Progressive MS
A progression of RRMS
• More common before advent of disease-modifying medications
• Approximately 50% of patients progressed to SPMS after 10-15 years with RRMS
• Incidence has since decreased
This disease course is steadily progressing.
Can present with or without clear-cut relapses.
See Graph!
PPMS
Primary Progressive Multiple Sclerosis
PPMS - Disease Overview
Primary-Progressive MS
Relatively rare, affecting 10% of patients.
Characterized by steady decline, without clear-cut relapses.
Medications are generally not effective at treating this type of disease.
PRMS
Progressive Relapsing Multiple Sclerosis
PRMS - Disease Overview
Progressive Relapsing Multiple Sclerosis
Relatively rare, affecting 5% of patients.
Steady disease progression, in addition to clear-cut periods of exacerbations of MS.
Patients can be treated for relapses with steroids, however disease will progress regardless of therapy
Treatment for Acute Exacerbation: Acute severe attack
Corticosteroids - NOT disease modifying
A hormone that stimulates the body to make its own hormone and improve its immune system ; Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.
*Methylprednisone (Solumedrol): 1 gram iv infusion per day x 3 to 5 days- may be followed by oral Prednisone taper 60 mg qd x 7 days, then 60 mg qod x 7 days, then 40 mg qod x 7 days, then 20 mg qod x 7 days, then stop
Side effects: jittery/increased energy (something MS patients aren’t used to)
H2 blocker/PPI for ulcer prophylaxis
Monitor blood glucose Watch for infection
Treatment for Acute Exacerbation: Acute severe attack (another option)
*Corticotropin Acthar gel: NOT disease modifying
Adrenocorticotropic hormone stimulates the adrenal cortex to secrete adrenal steroids (including cortisol), weakly androgenic substances, and aldosterone
Intramuscular or Subcutaneously: 80 to 120 units/day for 2 to 3 weeks
ABCR Injectables - Class of Medications
Interferon Beta
Glatiramer Acetate (pretty sure)
Disease Modifying Agents
Interferon beta - Drug Class and MoA
ABCR Injectables
MoA: not fully defined. It may augment suppressor T-cell function; may decrease interferon gamma secretion by activated lymphocytes; may decrease macrophage activating effect; may down-regulate expression of major histocompatibility complex gene production on antigen presenting glial cells.
May also suppress T cell proliferation and decrease blood brain barrier permeability
Interferon beta indication
RELAPSING forms of MS including clinically isolated syndrome, RRMS, and “active” SPMS
Avonex
Interferon beta-1a
30mcg IM injection dosed weekly
Can titrate to 30mcg to avoid flu-like symptoms
Rebif
Interferon beta-1a
SubQ injection TIW
22 or 44 mcg dose
Plegridy
Interferon beta-1a
SubQ injection every 14 days
Dose titration up to 125mcg
Plegridy® is pegylated interferon which refers to polyethylene glycol attached to interferon molecules to allow them to maintain their biologic effects in the body for a longer period of time
Betaseron
Interferon beta-1b
SubQ injection QOD
250mcg dose after titrating over 6 weeks
Extavia
Interferon beta-1b
SubQ injection QOD
250mcg dose after titrating over 6 weeks
Interferon beta side effects
FLU LIKE SYMPTOMS - up to 60% of patients. Pre-medicate with Tylenol/ibuprofen to alleviate
Generally worse in females and those with lower body weight
**Depression (not best agent if pt has uncontrolled depression)
Injection site reactions, HA, fever, myalgia, malaise, etc.
Glatiramer acetate
Mechanism of Action = Not fully known, thought to be related to alteration of T-cell activation and differentiation. Glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery (potential MoA). May mimic antigenic properties of myelin basic protein; May bind to Major histocompatibility complex class II receptors and inhibit binding of myelin basic protein peptides to T cell receptor complexes; May induce Th2 antiinflammatory lymphocytes and
decrease inflammation, demyelination, and axon damage.
Available as Copaxone,® Glatopa
– Subcutaneous injection given once daily
Glatiramer acetate indication
RELAPSING forms including clinically isolated syndrome, RRMS, and active SPMS
Side note: Is NOT an interferon beta agent, is an ABCR injectable
Difference between active and inactive SPMS
Some neurologists don’t believe in relapsing nature of SPMS.
Active denotes those with SPMS that relapse
Humanized monoclonal antibody
Murine complement sequence only
Chimeric monoclonal antibody
Murine antigen binding domain and complement sequence
(See image in notes)
Natalizumab MoA & Brand Name
Tysabri
Mechanism of Action = Antagonizes α4-integrin of the adhesion molecule very late
activating antigen (VLA)-4 on leukocytes. Binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4- mediated adhesion of leukocytes to their counter-receptor(s).
**Prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. Think of patho of MS (“leaky BBB” that allows body’s natural immune response to target myelin)
Even more effective than interferon beta agents for efficacy
Tysabri
Natalizumab
• A humanized monoclonal antibody.
• Intravenous infusion given once every 4 weeks
• Dose = 300 mg
Tyruko
Natalizumab=sztn biosimilar to Tysabri
Natalizumab indication
RELAPSING forms including clinically isolated syndrome, RRMS, and active SPMS
Natalizumab Side Effects
**Progressive Multifocal Leukoencephalopathy (PML) = a sometimes fatal viral opportunistic infection
– Results from activation of the latent John Cunningham polyomavirus in immunocompromised pts
– PML is a demyelinating disease similar to MS, causing impairment of the transmission of nerve impulses, however once myelin is lost in PML, it cannot be regained.
TOUCH Prescribing Program - MRI and symptom monitoring required due to PML risk
Other SEs: infusion rxn, UTI, respiratory tract infection, depression, HA, fatigue, etc.
Which agents can cause PML?
- Natalizumab
- Fingolimod
- Dimethyl Fumarate
Three risk factors for developing PML
- testing positive for antibodies to JCV (John Cunningham Virus, human polyomavirus 2)
- prior use of certain immunosuppressant medications
- using natalizumab for more than 2 years
Alemtuzumab Brand Name
Lemtrada
Alemtuzumab MoA
Lemtrada
Mechanism of Action = humanized monoclonal antibody. Targets CD52 on T and B lymphocytes, natural killer cells, macrophages and monocytes, causing long-term reduction of circulating T-cells
Alemtuzumab Indication
Lemtrada
Indicated for RELAPSING forms of MS, generally reserved for inadequate response to 2 or more (disease modifying) medications
Alemtuzumab Administration
Lemtrada
“A reset on the patient’s immune system”
12 mg infused *IV daily over 4 hours for 5 days, then a 3 day course at month 12; patients are observed 2 hours after infusion. Patients can be re-treated again for another 3 days after 12 months
*Premedicate with corticosteroids (methylprednisolone 1,000 mg or equivalent)
* Antihistamines and/or antipyretics may also be considered. Administer antiviral prophylaxis (for herpetic viral infections (16% vs 3% interferon)) beginning on the first day of treatment and continue for at least 2 months after completion of alemtuzumab and until CD4+ lymphocyte count is ≥200/mm3
Alemtuzumab Side Effects
Lemtrada
*DEVELOPMENT OF Autoimmune THYROID DISORDERS
Including GRAVES’ DISEASE requiring thyroid ablation
In 1/3 of patients
For MS, monitor TSH at baseline and every 3 months until 48 months after last infusion or longer or at any time during therapy if clinically indicated.
*Rash in 90% of patients
Others: infections, dizziness, HA, N/V/D, etc.
Alemtuzumab BBW
Lemtrada
BBW:
- autoimmune conditions, such as immune thrombocytopenia and anti-glomerular basement membrane disease.
- ischemic/hemorrhagic stroke within 3 days of dose admin
- Infusion reactions (Lemtrada): Alemtuzumab causes serious and life-threatening infusion reactions (92%). must be administered in a setting with appropriate equipment and personnel to manage anaphylaxis or serious infusion reactions. Monitor patients for 2 hours after each infusion.
- Malignancy
Alemtuzumab Monitoring
Lemtrada
CBC with differential prior to initiation then monthly until 48 months after last infusion; serum
creatinine prior to initiation then monthly until 48 months after last infusion or at any time during
therapy if clinically indicated;
Urinalysis with urine cell counts (prior to initiation then monthly); signs/symptoms of infection;
TSH at baseline and every 3 months until 48 months after last infusion or longer or at any time during therapy if clinically indicated;
Observe for at least 2 hours after each infusion, longer if clinically indicated;
ECG prior to each treatment course
No live vaccines, wait 6 weeks after VZV
Annual HPV screening (2%)
Signs/symptoms of PML
Baseline and annual skin exams (for melanoma).
Daclizumab
Taken off the market
Anti CD 20 Monoclonal Antibodies
Ocrelizumab
Ublituximab
Ofatunumab
Ocrelizumab Brand Name
Ocrevus
Ocrelizumab MoA, RoA
Ocrevus
Monoclonal Antibody
MOA: binds to (CD20) on the surface B cells, and depletes them from circulation
RoA: IV 600mg every 6 months (after 300mg OD1 and 300mg 2 weeks later)
Similar to rituximab, but
• Increased antibody-dependent, cell-mediated cytotoxic effects.
• Potentially less immunogenic
Ocrelizumab Indication
Ocrevus
Significantly reduce relapse rates, disability progression and disease activity on MRI in patients with RRMS and SPMS
Reduce disability progression 24%, time required to walk 25 feet, volume of brain lesions and whole brain volume loss in PPMS in the ORATORIO phase III trial. This is the first large scale trial to show positive results in PPMS
Indication: PPMS and relapsing forms of MS, including CIS, RRMS, and active SPMS
(Didn’t remember the ** parts? Mark this as wrong!)
Ocrelizumab Side Effects
Ocrevus
Most common adverse events = INFUSION REACTIONS
Patients were PRE-MEDICATED with *steroids (methylprednisolone 100 mg IV 30 min prior), *antipyretics (APAP), and *antihistamines (diphenhydramine 30-60 min prior)
Ocrelizumab Contraindications/Warnings
Ocrevus
CI: active hepatitis B virus (HBV) infection. Screen patients before starting
NO cases of PML found in studies with Ocrelizumab
Ublituximab Brand Name
Biumvi
Ublituximab MoA + Indication
Biumvi
MoA: chimeric IgG monoclonal antibody directed against the CD20 antigen on pre-B and mature B lymphocytes. Ublituximab binds to CD20 and results in cell lysis via complement-dependent cytolysis and antibody-dependent cellular cytolysis.
Indication: relapsing forms of MS including CIS, RRMS, active SPMS
Ublituximab Safety, Contraindication(s) and Administration
Biumvi
Safety: screen all patients for hepatitis B virus, hepatitis B core antibody, and latent infections. Pregnancy testing recommended before each dose.
CI: Active HBV infection (think uBlituximab, no Hep B!)
Administration: PREMEDICATE with methylprednisolone 100mg IV, antihistamine, and may consider antipyretic (acetaminophen) all ~30 minutes prior to dose
Given IV 150mg OD1, 450mg 2 weeks later, then 450mg q24 WEEKS
Ublituximab Warnings/Precautions
PML
Polysorbate 80 (ingredient, not a main focus)
Immunizations (live 4 weeks before, non-live 2 weeks before, no live or live attenuated during treatment or after D/C until B-cell repletion)
Ofatunumab Brand Name
Kesimpta
Ofatunumab MoA and Administration
Kesimpta
MoA: Ofatumumab is a monoclonal antibody which binds specifically the extracellular (large and small) loops of the CD20 molecule (which is expressed on normal B lymphocytes and in B-cell CLL) resulting in potent complement-dependent cell lysis and antibody-dependent cell-mediated toxicity in cells that overexpress CD20.
Administer all live or live-attenuated vaccines at least 4 weeks prior and non-live vaccines at least 2 weeks prior to initiation of therapy. Screen for hepatitis B prior to initiation; do not administer to patients with active hepatitis B confirmed by hepatitis B surface antigen (HBsAg) and anti-hepatitis B virus (HBV) tests.
Administer only by SubQ injection in the abdomen, thigh, or outer upper arm one time per MONTH. Patients may self administer
Ofatunumab Warnings/Precautions and Adverse Effects
Kesimpta
Warnings: Females of reproductive potential should use effective contraception during therapy and for 6 months after the last dose of ofatumumab.
PML risk
Adverse Effects: Infection (52%) and URTI (39%)
Which agents are considered chemotherapy drugs used in MS?
Mitoxantrone
Cladribine
Mitoxantrone Brand Name
Novantrone
Mitoxantrone MoA and Indication
Mechanism of Action = Intercalates with DNA strands causing breaks, and inhibits DNA repair through topoisomerase II.
– Affects rapidly dividing cells -> secondary effects on the immune system
**Indication: SPMS, PRMS, or worsening of RRMS to reduce neurologic disability and/or the frequency of clinical relapse
**Limitation of use: not indicated for the treatment of PPMS. Reserve use for rapidly-advancing, refractory multiple sclerosis
Different indication than other agents!
Mitoxantrone Administration and Side Effects
Novantrone
Chemically related to doxorubicin and daunorubicin
Positive Evidence of Risk (Pregnancy Category D)
– Intravenous infusion given once every 3 months
Side Effects: Cardiotoxicity , bone marrow suppression, others…
Cladribine Brand Name
Mavenclad
(2-chlorodeoxyadenosine)
Mavenclad (cladribine) MoA and Indication
Treatment of relapsing forms of multiple sclerosis, (RRMS) and active SPMS in adults who have had inadequate response or are intolerant to other therapies for multiple sclerosis. Must have failed something else
Not recommended for patients with clinically isolated syndrome
MoA: Cladribine is a purine nucleoside analogue; it is a prodrug which is activated by phosphorylation and converted into the active moiety, Cd-ATP. This active form incorporates into DNA to result in the breakage of DNA strand and shutdown of DNA synthesis and repair. This also results in a depletion of nicotinamide adenine dinucleotide and adenosine triphosphate (ATP). Cladribine is cell-cycle nonspecific. The mechanism of cladribine in treating multiple sclerosis (MS) is unknown, but may involve cytotoxic effects on B and T lymphocytes that result from the shutdown of DNA synthesis, leading to a depletion of lymphocytes.
Mavenclad (cladribine) Administration and Safety
10 mg ORAL tablets
Usual dosage: 3.5 mg/kg over 2-year treatment course, administered as 1.75 mg/kg in each year.
• Divide the 1.75 mg/kg dose over 2 cycles, each cycle lasting 4 to 5 consecutive days
Lymphocytes must be within normal limits before initiating first treatment course and ≥800 cells/mm3 before initiating the second treatment course.
Patients should use dry hands for handling and avoid prolonged contact with skin; wash hands and any surface that came in contact with the tablet thoroughly afterwards. Separate administration from any other oral medication by 3 hours.
Hazardous agent (NIOSH 2016 [group 1]).
Mavenclad (cladribine) Boxed Warnings / Contraindications
*Malignancies (cancer)
*Teratogenicity - CI in pregnant women. women/men of reproductive potential - use effective contraception during cladribine oral tablets dosing and for 6 months after the last dose
HIV infection
Active Chronic Infections (e.g. hepatitis or tuberculosis)
Low MW and Low protein binding = likely crosses into breast milk
Mavenclad (cladribine) Warnings/Precautions
Malignancy + Pregnancy (boxed warning)
Bone Marrow Suppression
Infection
PML
Vaccines
Graft-versus-Host Disease
Hepatotoxicity
Cardiotoxicity
Drug Interactions
Substrate of BCRP/ABCG2, P-glycoprotein/ABCB1
Mavenclad (cladribine) Monitoring
- CBC including lymphocyte count (before each treatment course, 2 and 6 months after the start of each yearly course)
- evaluate HIV, tuberculosis, hepatitis B (HBV) and hepatitis C (HCV) status (prior to each treatment course);
- evaluate varicella-zoster virus (VZV) antibody status (prior to treatment initiation);
- pregnancy test (prior to treatment in females of reproductive potential);
- liver function tests (serum aminotransferase, alkaline phosphatase and total bilirubin levels) (prior to each treatment course and as clinically appropriate)
- MRI (at baseline [within 3 months] prior to first treatment course); signs or symptoms of progressive multifocal leukoencephalopathy (PML)
- standard cancer screening;
- signs or symptoms of acute infection.
S1P Drugs
All ORAL agents
Fingolimod
Siponimod
Ozonimod
Fingolimod Brand Name and Bioequivalent Product
Gilenya
Tascenso ODT = bioequivalent to Gilenya
Fingolimod MoA and Indication
Gilenya
Mechanism of Action = Acts on the sphingosine-1-phosphate (S1P) receptors S1P1 and S1P3-5 on the surface of lymphocytes
-Depletes both CD4+ and CD8+ T lymphocytes in the blood stream, up to 75% below baseline.
-CD4+ cells are decreased to a greater extent than CD8+ cells.
-Inhibits lymphocyte release from lymphatic organs decreasing overall numbers in circulation
Note: they’re still there, just contained in lymphatic organs
Indication: relapsing forms of multiple sclerosis, including CIS, RRMS, and active SPMS, in patients ≥10 years of age
Fingolimod Administration, Monitoring, Side Effects
Gilenya
ORAL Therapy for MS, 0.5mg PO QD
First Dose Monitoring: ECG needed before initiating. Monitor hourly for 6 hrs post 1st dose for bradycardia— take HR and BP
* Repeat 1st dose monitoring if patient misses 1 day in first 2 weeks, 7 days in 3rd and 4th weeks, or 14 days after 1 month
Contraindicated: recent MI, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, Class III or Class IV heart failure. history of Mobitz Type II second or third degree AV block or sick sinus syndrome (unless patient has a pacemaker), baseline QTc greater than 500 msec, or with concurrent treatment with Class Ia or Class II anti-arrhythmic drugs
Patients without antibodies who wish to become vaccinated against varicella zoster should wait 30 days after vaccination before receiving fingolimod as patients on fingolimod should not receive live vaccines.
Macular Edema (pt should receive baseline eye exam and checkups), other common AEs
Siponimod Brand Name
Mayzent
Siponimod MoA and Indication
Mayzent
Treatment of relapsing forms of multiple sclerosis (MS), including CIS, RRMS, and active SPMS, in adults
MoA: a sphingosine-1-phosphate (S1P) receptor modulator, binds to sphingosine 1-phosphate receptors 1 and 5. Siponimod blocks the lymphocytes’ ability to emerge from lymph nodes; therefore, the amount of lymphocytes available to the CNS is decreased, which reduces central inflammation
Siponimod Dosing
Mayzent
ORAL Dosing - patient MUST undergo genotype testing (2C9 - NINE)
CYP2C9 Genotype 1/1, 1/2, or 2/2
Maintenance dosage: 2 mg QD, beginning on Day 6
CYP2C9 Genotype 1/3 or 2/3
Maintenance dosage: 1 mg QD, beginning on Day 5
CYP2C93/3 genotype contraindicated
First dose monitoring recommended, but NOT required like for fingolimod
Siponimod Contraindications
Contraindications: CYP2C93/3 genotype; recent (in the past 6 months) MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure; Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker
Siponimod Warnings/Precautions
Mayzent
* Immunizations: Testing antibodies to (VZV) is recommended prior to initiation of treatment if history of chickenpox or VZV vaccination status is unknown* Wait 4 weeks for live vaccination
Infections
PML
Macular Edema - just like fingolimod
Atrioventricular conduction delays
QT Prolongation
CVD, HTN, Bradycardia
Respiratory/Hepatic Effects
Neurotoxicity
Malignancy
DDIs
* Discontinuation of therapy - Cases of rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected) have been reported with discontinuation of another sphingosine 1-phosphate receptor modulator
Siponimod DDIs
Mayzent
Drug-drug interactions Extensively metabolized, mainly via CYP2C9 (79.3%), followed by
CYP3A4 (18.5%) to inactive metabolites, M3 and M17
Immunosuppressants
Bradycardia-causing agents
AV blocking agents
QT prolonging agents
2C9/3A4 inducers may decrease concentration
2C9/3A4 inhibitors may increase concentration
Siponimod Use in Pregnancy, How long to use contraception?
Mayzent
No. May cause fetal harm. Disease modifying therapies are generally not initiated during pregnancy . Females of reproductive potential should use effective contraception during therapy and for 10 days after the last siponimod dose.
~2 months for Fingolimod
~3 months for Ozonimod
Siponimod Monitoring
Mayzent
All patients: CBC including lymphocyte counts, hepatic, ecg, ophthalmic exam, respiratory function, VZV antibodies, BP, s/s infection or PML, suspicious skin lesion monitoring
First dose monitoring only in select patients:
Additional required monitoring for patients with sinus bradycardia (HR <55 bpm), first- or second-degree (Mobitz type 1) AV block, or a history of MI or heart failure
Ozonimod Brand Name
Zeposia
What is Progressive Multifocal Leukoencephalopathy?
Cases of progressive multifocal leukoencephalopathy (PML) due to the John Cunningham virus have been reported in patients taking sphingosine 1- phosphate receptor modulators. Risk factors for development of PML include HIV, AIDS, cancer history, rheumatologic disease history, persistent lymphocytopenia, sarcoidosis, and prior immunosuppressant use (Jamilloux 2014; Tan 2010). At the first sign or symptom suggestive of PML, perform a diagnostic evaluation and withhold therapy; symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and mental status changes. Cases of PML have been diagnosed based on MRI findings without specific PML signs/symptoms. Monitoring with brain MRI for signs that may be consistent with PML may be beneficial and allow for an early diagnosis of PML. Discontinue treatment if PML is confirmed.
Ozonimod MoA, Administration, CI
Zeposia
Lots of duplicate info from other S1P drugs, will highlight main differences on other Ozonimod cards
MoA: Ozanimod has a high affinity to sphingosine 1-phosphate receptors 1 and 5. Ozanimod blocks the lymphocytes’ ability to emerge from lymph nodes; therefore, the amount of lymphocytes available to the CNS is decreased.
Administration: ORAL Dosing. Maintenance dose: 0.92 mg once daily starting on day 8. Note: If a dose is missed during the 2-week titration period, reinitiate the titration regimen with 0.23 mg once daily. If a dose is missed after the first 2 weeks of treatment continue with treatment as planned.
If live attenuated vaccine immunizations are required prior to administration, initiate ozanimod therapy at least 1 month following immunizations
Contraindications: Myocardial infarction, unstable angina, stroke, transient ischemic attack,
decompensated heart failure (HF) requiring hospitalization, or class III or IV HF in the last 6
months; Mobitz type II second- or third-degree atrioventricular block, sick sinus syndrome, or
sinoatrial block, unless the patient has a functioning pacemaker; severe untreated sleep apnea;
concomitant use of a monoamine oxidase inhibitor
Use of Ozonimod in pregnancy
Females of childbearing potential should use effective contraception to avoid pregnancy during therapy and for 3 months after discontinuing treatment.
Fingolimod ~2 months
Siponimod 10 days
Ozonimod - Most Unique Point
Zeposia
* Concurrent ingestion of foods and beverages with very high amounts of tyramine (ie, >150 mg) may cause sudden and severe high BP (hypertensive crisis). Management: Avoid foods with very high tyramine content.
***Contraindicated in use with MAOi’s (selegiline, rasagiline, isocarboxazid, etc.)
Clinical trials show Versus Avonex, (maybe important to know?)
Decreased ARR
Decreased Gd+ lesions
Decreased new or enlarging T2 lesions
Ponesimod Brand Name
Ponvory
Ponesimod Class and Unique Points
Ponvory
Sphingosine 1-phosphate (S1P) receptor 1 modulator, binds with high affinity to S1P receptor 1.
Cardiac monitoring: First-dose 4-hour monitoring is recommended for patients with certain preexisting cardiac conditions, including sinus bradycardia (heart rate <55 bpm), first- or second-degree (Mobitz type 1) atrioventricular block, or a history of myocardial infarction or heart failure ≥6 months prior to initiation
Don’t start in active infection, like with other S1P receptor modulators
Missed dose: ≥ 4 consecutive doses missed: Reinitiate treatment with day 1 of the initial titration regimen, including first-dose monitoring when appropriate.
Ponesimod (unique/emphasized) Significant AEs
-Basal cell carcinoma and other skin malignancies (including malignant melanoma and squamous cell carcinoma of the skin) have occurred rarely with ponesimod.
-Increased serum transaminases have been observed with ponesimod therapy, primarily as increased serum alanine aminotransferase (ALT), including increases up to 5 x ULN.
-Reversible lymphocytopenia occurs during ponesimod therapy. Infection is commonly observed with use, typically upper respiratory tract infection and less commonly urinary tract infection; viral infections (eg, herpes virus infection) have also been observed
-Reduced forced expiratory volume over 1 second (FEV1) and reductions in diffusion lung capacity for carbon monoxide have occurred with ponesimod therapy
Teriflunomide Brand Name
Aubagio
Teriflunomide MoA and Indication
Aubagio
Blocks pyrimidine synthesis in rapidly dividing cells, inhibits protein tyrosine-kinase and cyclo-oxygenase-2 activity, and decreases the ability of antigen presenting cells to activate T-cells.
Inhibition of pyrimidine synthesis selectively produces a cytostatic effect on proliferating T and B lymphocytes in the periphery, while avoiding undue cytotoxicity to other cell types. Teriflunomide effectively reduces B-lymphocyte proliferation
Indication: oral therapy for RRMS and SPMS - Doses = 7 and 14 mg
Also says for CIS on Lexicomp
Teriflunomide Side Effects and BBW
Aubagio
Lots of SEs, Highlighted in class:
*Alopecia
*Increases in LFTs
BBW: Hepatotoxicity, teratogenicity – Category X for Pregnancy
Teriflunomide Elimination Agent
Aubagio
Accelerate elimination with cholestyramine 8 or 4 g q 8h x 11d or
50 g activated charcoal q12 h x 11 d
– Decrease conc by 98%
– Without reversal agent, the drug lasts in the body for 8 mo-2 years
Teriflunomide Important DDIs
Aubagio
**The dose of rosuvastatin should not exceed 10 mg in patients on teriflunomide.
Teriflunomide may decrease INR in patients taking warfarin.
Fumarates
Dimethyl fumarate (Tecfidera)
Diroximel fumerate (Vulmerity)
Monomethyl fumerate (Bafiertam)
Dimethyl fumarate Brand Name and MoA
Tecfidera
MoA: Induces T-helper 2-like cytokines (including interleukins 4, 5, and 10) causing
– Apoptosis in activated T cells and
– Down-regulation of intracellular adhesion molecules, leading to reduced migration of lymphocytes.
DMF and its active metabolite, monomethyl fumarate (MMF), have been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in cellular response to oxidative stress
Dimethyl fumarate indication, dosing, and study results
Tecfidera
Approved as an oral therapy for relapsing forms of MS including CIS, RRMS, and active SPMS
Dose = 120mg PO BID for 7 days, then 240mg PO BID
Dimethyl fumarate treatment decreased number of new T1, new T2, and Gd+ lesions on MRI
Dimethyl fumarate Side Effects
Tecfidera
GI SYMPTOMS!!! Administer with or without food; administering with high-fat, high-protein food (eg, yogurt or peanut butter) may decrease the incidence of flushing and GI effects
Flushing - Administration of aspirin (nonenteric coated up to a dose of 325 mg) 30 minutes prior to dimethyl fumarate may also reduce the incidence of flushing
Transient increases in LFTs
Lymphopenia
– Recent CBC (within 6 months) needed before treatment, then q 3 mo therafter and as
clinically indicated.
– Lymphocyte count <500/mm3 persisting for >6 months: Consider treatment interruption.
– MRI (baseline and as clinically indicated to monitor for early signs of progressive multifocal
leukoencephalopathy [PML]).
Diroximel Fumerate Key Points
Vumerity
-Bioequivalence to dimethyl fumarate (Tecfidera)
-Maintenance dose of 462 mg twice daily.
-Unique structure that rapidly converts to monomethyl fumarate in the body. As a result, the drug causes less gastrointestinal (GI) irritation
-May administer aspirin (nonenteric coated ≤325 mg) 30 minutes prior to diroximel fumarate to reduce the incidence or severity of flushing.
-A high-fat (>30 g), high-calorie (>700 calories) meal may significantly DECREASE the maximum concentration of the major active metabolite, monomethyl fumarate (MMF)
Monomethyl fumerate key points
Bafiertam
-“Bioequivalent alternative” to Biogen’s Tecfidera® (dimethyl fumarate) - site of action and active ingredient don’t differ significantly
-Maintenance dose: 190 mg twice daily
-Non-enteric coated aspirin up to 325mg can be used for flushing
**Unique to this product: Store unopened bottles in refrigerator , opened at room temp
Symptoms of MS
Spasticity
OAB/Urinary Retention
Sensory (paresthesias, neuropathic Pain)
Fatigue/cognitive issues/ Emotional issues
Pseudobulbar Affect (PBA)
Walking
Spasticity in MS Treatment
Antispasmodics
• Baclofen
• Dantrolene
• Diazepam, clonazepam
• Tizanidine
• Gabapentin, tiagabine, pregabalin
• Botox
• Dalfampridine
(Not sure we have to know all these)
Bladder (OAB/Urinary Retention) in MS Treatment
Recall: MS patients have cognitive impairment, beware which agents you choose!
(Just skim through)
• Propantheline - Propantheline bromide inhibits gastrointestinal motility and diminishes gastric acid secretion. The drug also inhibits the action of acetylcholine at the postganglionic nerve endings of the parasympathetic nervous system
• Oxybutynin - antimuscarinic
• Dicyclomine/Bentyl - Dicyclomine is an antispasmodic and anticholinergic (antimuscarinic) agent
• DDAVP - DESMOPRESSIN ACETATE ( 1-Deamino-8-D-Arginine Vasopressin), Desmopressin is a
synthetic analog of the natural pituitary hormone arginine vasopressin, an antidiuretic hormone
affecting renal water conservation
• Cathetherization
• Imipramine/amitriptyline
• Prazosin -inhibits postsynaptic alpha-adrenergic receptors
• Botox
• Solifenacin/Vesicare - anticholinergic
• Darifenacin/Enablex - anticholinergic
• Trospium / anticholinergic
• Hyoscyamine - anticholinergic
• Fesoterodine/Toviaz– anticholinergic
• Mirabegron (Myrbetiq) is a novel selective human beta-3-adrenergic receptor agonist that relaxes the detrusor smooth muscle and increases bladder storage capacity. It has been shown to be efficacious in a small study of MS patients who has previously experienced low efficacy with antimuscarinics
Sensory (paresthesias, neuropathic Pain) in MS Treatment
• Carbamazepine, oxcarbazaepine
• Phenytoin
• TCAs
• Gabapentin
• Lamotrigine
• Pregabalin
• Duloxetine
Fatigue/cognitive issues/ Emotional issues in MS Treatment
• Amantadine
• SSRI/SNRI
• Modafanil
• Methylphenidate
• Dextroamphetamine
Pseudobulbar Affect (PBA)
Characterized by uncontrollable episodes of crying or laughing
Treatable by Nuedexta (Dextrometorphan HBr and Quinidine Sulfate) 20/10mg 1 cap PO BID maintenance dose
Exact MoA unknown, thought to inhibit glutamatergic neurotransmitter via action at variety of locations including NMDA receptor and sigma-1 receptors
- Quinidine helps with blocking metabolism of dextrometorphan (2D6), therefore increasing serum concentrations of dextromethorphan (1-3% of dose used to treat cardiac arrhythmias)
Walking in MS Treatment
Dalfampridine (Ampyra) – (4-aminopyridine)
Dose: 10 mg BID - Tablets should only be taken whole
*Broad-spectrum potassium channel blocker
*Increase conduction of action potentials in demyelinated axons through inhibition of potassium channels
Contraindicated: History of seizure; Moderate to severe renal impairment (was on our first exam!)
Cannabinoids
Schedule 1 Federal Controlled Substance - makes research with it harder
Strong evidence OCE (oral cannabinoid extracts) in spasticity scores
Strong evidence OCE in central pain
Summary, cannabinoids may be effective for spasticity, MS-related pain, painful spasm, and bladder voiding. Cognitive impairment, can deter product use, particularly in patients already experiencing cognitive difficulties.
Only medication approved for PPMS?
Ocrelizumab (Ocrevus) - CD20 mab
Provider wants a CD-20 agent for their MS patient, but wants an agent the patient can self administer under the skin. Which agent?
Ofatunumab (Kesimpta)
